Doxorubicin reduced intermediate HDL particles by ~4% and PON1 activity, correlating with decreased LVEF and impaired HDL protection against cardiotoxicity in breast cancer.
Does doxorubicin chemotherapy alter HDL particle subclasses and function, and does this correlate with cardiac dysfunction in breast cancer patients and tumor-bearing mice?
Doxorubicin chemotherapy induces a shift in HDL particle subclasses and a loss of their protective functionalities, which correlates with cardiac dysfunction in breast cancer patients and tumor-bearing mice.
Absolute Event Rate: 0% vs 0%
Abstract Background Cancer patients receiving doxorubicin (DOX) chemotherapy are at high risk of developing cardiotoxicity, but the mechanisms remain elusive. Both breast cancer and DOX treatment are associated with dyslipidemia. Objectives We aimed to investigate whether changes in High Density Lipoprotein (HDL) particles subclass distribution and functionalities in breast cancer patients and tumor-bearing mice may be associated with DOX-induced cardiac dysfunction. Methods HDL particles subclasses were assessed using the Lipoprint® system in breast cancer patients (n=34) and in healthy (control) or tumor-bearing mice at baseline (B) and after (E) receiving DOX chemotherapy (see picture 1). HDL particles anti-oxidative property was assessed by measuring paraoxonase-1 (PON1) activity. The ability of isolated HDL particles to protect against DOX-induced cytotoxicity was assessed in H9c2 cells by measuring cytoplasmic ATP levels. Results In breast cancer patients, DOX therapy reduced percentage in intermediate HDL particle subclasses (from 52.5±-1.0% (B) to 48.6±0.9% (E), p=0.007), an effect that positively correlated with a decrease in left ventricular ejection fraction (p0.04). In mice, breast cancer reduced the percentage of intermediate HDL particles (Control: 74.1±1.4% vs Tumor: 66.8±2.5%, p0.05) and increased the percentage of large HDL particles (Control:25.5±1.5% vs Tumor:32.5±2.6%, p0.05) while DOX treatment increased small HDL particles by 80.5% (p=0.03). Both breast cancer and DOX treatment were associated with reduced PON1 activity (Control: 0.35±0.04U/L vs DOX+Tumor: 0.22±0.03U/L, p0.05). Changes in PON1 activity correlated with the percentage of intermediate HDL particles (r = +0.53, p0.05). In addition, the percentage of intermediate HDL particles subclasses (HDL-6 and HDL-7) were associated with changes in left ventricular ejection fraction (p0.01). Most importantly, HDL particles isolated from tumor-bearing mice or from mice receiving DOX fail to protect H9c2 cells against DOX-induced cytotoxicity compared to HDL particles of healthy mice (DOX:49.3±11.9% or Tumor:55.4±19.1% vs Control:100±16.6%, p0.05). Conclusion This study highlights that a shift in HDL particles subclasses and a loss in their functionalities directly correlate with cardiac dysfunction in cancer patients/mice treated with DOX. Consequently, our data warrant further research to explore how targeting HDL particles may represent a therapeutic strategy to limit DOX-induced cardiotoxicity in breast cancer patients.Experimental Protocol
Abrahams et al. (Sat,) reported a other. Doxorubicin reduced intermediate HDL particles by ~4% and PON1 activity, correlating with decreased LVEF and impaired HDL protection against cardiotoxicity in breast cancer.
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